Retinal degenerative disease and injury are among the leading causes of irreversible vision loss and blindness in the United States and the developed world, affecting hundreds of thousands of people every year and resulting in billions of dollars in added healthcare costs and lost productivity. Photoreceptor cell death is a consequence of many of these acute and chronic retinal diseases, leading to vision loss, and helping photoreceptors survive during the period of disease would significantly improve the visual outcomes for patients. A problem that limits the efficacy of current treatments is the lack of interventions that can specifically prevent photoreceptor cell death; therefore, a safe and potent photoreceptor protectant would provide a significant visual benefit to hundreds of thousands of people every year. ONL1204 is a novel, small peptide inhibitor of Fas-mediated photoreceptors cell death in development for peri-operative adjunctive use in patients with acute retinal detachment (an orphan indication for which ONL1204 has received an orphan drug designation) with the goal of preventing photoreceptor cell death until definitive surgical repair can occur. This acute indication provides a rapid development pathway that lays the groundwork for future expansion of ONL1204 development for chronic indications, such as age-related macular degeneration. The product for acute retinal detachment will be a prescription drug administered by intravitreal injection. Completion of the proposed studies in this grant will help ONL Therapeutics address final investor questions and attract the significant financial investment required for IND submission and clinical development of ONL1204. Specifically, in this grant, we will 1) determine the minimal dose of ONL1204 required for photoreceptor protection and preservation of function in large eye animal models of retinal detachment, and 2) demonstrate the GLP safety and tolerability of a single intravitreal injection of ONL1204 at clinically meaningful doses. The studies proposed in this application are necessary for development and commercialization of ONL1204, will de-risk the program, and enable significant financial investment, allowing ONL Therapeutics to evaluate clinical POC for ONL1204 in retinal detachment.